Meniscal degeneration is typically associated with cartilage degeneration in advanced osteoarthritis (OA) of the knee, but the relationship between meniscal degeneration in the onset and progression of knee OA remains unclear. Meniscal tears have long been recognized as a contributing factor to knee OA, primarily due to changes in joint biomechanics that result in local increases or decreases in the mechanical stress on the cartilage. However, a variety of recent findings suggest that degenerative meniscal changes, regardless of whether or not they tear, may be an early event in the development of knee OA. Despite the growing indications of the importance of asymptomatic meniscal degeneration, however, relatively little is currently known regarding the mechanisms contributing to meniscal degeneration or the reasons why meniscal lesions appear to precede cartilage degeneration. The parent grant for this proposal (R01AR052861, Spatiotemporal Progression of Meniscal Degradation) addresses this gap in knowledge by examining the effects of biochemical and biomechanical induction of meniscal degradation using in vitro model systems. Results to date indicate that meniscal cells aggressively degrade the extracellular matrix (particularly the proteoglycans in the matrix compartment surrounding the primary collagen bundles) when stimulated by interleuken-I, and that matrix metalloproteinases play a greater and earlier role in meniscal degradation than in cartilage degradation. Importantly, this proteoglycan degradation leads to rapid and dramatic reductions in functional biomechanical properties of the tissue. Noninvasive detection of meniscal regions exhibiting proteoglycan depletion could thus identify regions of impaired mechanical function, providing novel opportunities for detection of early-stage knee degeneration and a potential target for monitoring the efficacy of early interventions. The proposed studies will involve an interdisciplinary research team with expertise in development of novel MRI strategies, clinical imaging of musculoskeletal soft tissues, and biochemical and biomechanical analysis of musculoskeletal soft tissues. The focus of this project will be to identify MRI imaging modalities that are capable of identifying degenerative meniscal lesions associated with impaired tissue biomechanics. Aim 1 will involve detection of lesions induced by controlled enzymatic degradation of healthy bovine menisci as a platform for identifying the most promising imaging modalities. Aim 2 will involve characterization of macroscopically intact human menisci obtained as surgical waste from total knee arthroplasties. The extent of MRI signal changes in specific regions will be compared to sulfated glycosaminoglycan content, levels of proteoglycan cleavage and biomechanical properties. The proposed studies will substantially extend the scope of the parent grant and will lay the groundwork for the development of novel clinical imaging strategies for noninvasive detection of functionally relevant meniscal lesions. [unreadable] [unreadable] [unreadable]